**7. Interferon genes are associated with lupus**

INF—is a protein produced mainly by dendritic cells and lymphocytes following a viral infection and links innate and adaptive immunity. It confers resistance to viral infection and susceptibility to autoimmunity. Previous studies showed that interferon type I is strongly associated with the pathogenesis of lupus. The primary pathogenic factor in SLE escalates IFN-a signaling, which can activate STAT4, a transcription factor [13]. Genetic variations of this transcription factor have been associated with the risk of SLE and rheumatoid arthritis. Immature pDCs are activated through innate toll receptors TLRs, TLR7 and TLR9 by immune complexes to produce inflammatory cytokines including type I INF. High levels of serum IFN type I together with overexpression of IFN inducible genes have been found in individuals with SLE. The level of IFN correlated with the severity of the disease. The top 10 genes identified, associated with excessive production of IFN in viral infection, are I STAT1, IRF7, IRF5, IRF8 MX1, OASL, ISG15, IFIT3, IFIT1, OAS2 and GBP1 [14]. Among those, all associated with SLE only GBP1 was of recent association with the disease IRF5, IRF7 and IRF8 a family of transcription factors downstream of endosomal TLRs, are required for activating transcription of IFN-a and IFN-inducible genes [15–17]. Genetic variants on these three genes but especially variants of IRF5 and IRF7 have a functional impact on increased serum IFN and such impact depends on the presence of specific autoantibodies. The type I interferon pathway is central to disease pathogenesis. Hydroxychloroquine acts therapeutically on lupus by inhibiting the interferon pathway [18].

## **8. Complement genes and lupus**

Evidence has revealed that complement deficiencies result in a reduced ability in the clearance of apoptotic cells that increase the production of autoantibodies and therefore SLE development in susceptible individuals. The C1q component – the first component of the classical complement pathway - that plays a significant role in the apoptotic cells is associated with SLE. C1q is encoded by three genes (a, b and c genes) all located in chromosome 1. The lupus autoantigens that are located in apoptotic debris may stimulate an inappropriate immune response. C1q may inhibit IFN-gamma production and, in this way, is involved in SLE development. When hereditary homozygous deficiency in any of the three C1q genes occurs, this leads to the development of SLE in all cases. C2, C4A and C4B genes which are part of the HLA class III genes – located at chromosome 6 – constitute components of the classical complement activation pathway. Observed in 0.01–0.02% of the general population C2 deficiency is the commonest but in lupus patients its prevalence is significantly higher depending on the region, 0.4% – 2.33% of people of European origin carry C2 deficiency – caused by a deletion on the DRW2 haplotype. These individuals will eventually develop lupus in their lifetime. C4 is important as a single gene defect. About 70% of the known cases of double homozygous C4 deficiency (C40, deficient at both C4A and C4B genes) result in a lupus phenotype. The C4A null allele is associated with almost every SLE population studied to date and may have an independent HLA effect [19].

#### **9. Fc-gamma receptor gene polymorphisms and lupus erythematosus**

The receptors for the Fc portion of IgG (FcγRs) play an important role in the clearance of immune complexes. They also present the modified antigen to the different populations of lymphocytes and are implicated in the modulation of inflammatory processes within the human immune system. Pre three families of FcγRs exist, the FcγRI, is the high-affinity receptor, while FcγRII and FcγRIII are low-affinity receptors. Failure of FcγR mediated clearance of immune complexes and control of inflammatory responses are thought to be predisposing factors for the development of SLE. The FCGR2/3 locus on chromosome 1q23.3 that encodes the low-affinity FcγRs is subject to both single nucleotide polymorphisms (SNP) and copy number variation (CNV). An SNP in the promoter region of FcγRIIb, also known as 2B.4, was found to be more frequently present in lupus [20].
